Novartis’s Entresto PARAGON-HF Miss Puts Large Commercial Opportunity At Risk
Executive Summary
Entresto has narrowly failed to hit the primary endpoint in a Phase III trial in heart failure with preserved ejection fraction, a potentially lucrative indication with no approved treatments.
Entresto, Novartis AG’s approved heart failure drug, has failed in a Phase III trial in an indication that promised to double the patient population for the product. The PARAGON-HF trial data have been keenly awaited as a key catalyst with the potential to lead to a big increase in sales and profitability of the dual-acting drug.
Entresto (sacubitril/valsartan), which is already approved to treat patients with heart failure with reduced ejection fraction (HFrEF), was being studied also for heart failure with preserved ejection fraction (HFpEF), an indication with a similar number of patients as HFrEF but with no approved treatment. However, the results of the 4,822-patient PARAGON-HF trial in HFpEF showed it narrowly missed the composite primary endpoint of reducing heart failure hospitalizations and cardiovascular death versus valsartan alone.
“Entresto’s failure to show a benefit in this subgroup will significantly stunt its future revenue growth, as it limits use to patients with HFrEF, which is already a predominately genericized market,” Datamonitor Healthcare analyst Hannah Cohen told Scrip. “Entresto only recently overcame recent barriers to uptake in the form of reimbursement delays and physicians’ reluctance to shift from established treatment practices.”
Hopes had been high for PARAGON-HF given the size of the unmet need and Entresto’s previous positive results in HFpEF in the Phase II PARAMOUNT trial, which showed the medicine reduced NT-pro-BNP, a biomarker for cardiac strain, to a greater extent than valsartan alone at 12 weeks, as well as being associated with an improvement in New York Heart Association (NYHA) class at 36 weeks. NYHA classification of heart failure assigns patients to one of four groups based on their limitations during physical activity, measured by shortness of breath and chest pain. (Also see "Heart failure hope for Novartis first-in-class neprilysin inhibitor" - Scrip, 26 Aug, 2012.)
Analysts had predicted that approval of Entresto for the additional indication of reducing cardiovascular death and hospitalizations in patients with HFpEF could have added billions of dollars to its annual peak sales. Entresto sales were $778m in the first half of 2019, representing an increase (at constant currencies) of 83% on the first half of 2018. The drug has lately enjoyed a boost in sales, exceeding $1bn for the first time in 2018 following a faltering start after its launch in 2015, and positive results from PARAGON-HF had been expected to drive further growth.
Peak Sales Pared
Peak annual sales of Entresto based on its HFrEF indication alone have been predicted to reach $3-4bn or more, with a label expansion to HFpEF potentially adding a further $2-2.5bn. That additional boost now looks to be at risk, even though Novartis says it plans to discuss next steps with regulators and clinical experts, suggesting it has not given up hope of winning expanded approval in HFpEF. Despite the missed endpoint in the PARAGON-HF study, Novartis said “the totality of the evidence from the trial” still suggested Entresto may have “clinically important benefits in HFpEF.”
Novartis will present details of PARAGON-HF at the European Society of Cardiology (ESC) congress in Paris in late August/early September. It declined to provide any further information for the time being.
“It was not entirely unexpected that Entresto failed to meet the primary endpoint of reduction in CV death and HF hospitalizations in the Phase III PARAGON-HF trial in HFpEF patients, since there are a plethora of failures that encompass clinical trials in this patient population,” commented Cohen. “Although it is currently unclear what clinically important benefits Entresto has in HFpEF, its narrow miss of statistical significance on the primary endpoint makes it highly unlikely that the FDA will support a label expansion in this indication.” However, she noted that Novartis “may consider pursing Entresto in a subgroup of HFpEF patients, if any showed potential in the Phase III trial.”
Credit Suisse analysts, meanwhile, flagged up the lost opportunity for improved profitability. “PARAGON was an important 2H19 catalyst for investors given the high unmet need in HF-PEF and existing commercial infrastructure for Entresto in HF-REF (reduced ejection fraction) which would have allowed a very high contribution margin on incremental sales,” they wrote in a 29 July reaction note. “While management intends to engage with regulators, we would be surprised if Entresto was able to see an approved label indication based on a failed P3 study. However, if the data at ESC shows signs of meaningful efficacy then we would expect some off-label use in HF-PEF given no therapies have been shown to work to date.”
“We expected it to be more difficult for Entresto to demonstrate efficacy in the preserved ejection fraction population because the patients' hearts are in better condition, making it harder to show a benefit. Novartis estimates that there are 1.7m patients with HFpEF in the EU and 2.5m such patients in the US,” wrote Jefferies analysts in a 29 July note, in which they also said they would expect an HFpEF indication on its label to boost Entresto sales by $2.5bn at peak by patent expiry.
HFpEF A Trickier Target
While in HFrEF the heart does not contract with enough force to pump out blood sufficiently, in HFpEF the heart contracts normally but the ventricles do not relax properly during ventricular filling. Novartis has said that around half of the estimated 13 million heart failure patients worldwide suffer from HFpEF. Unfortunately, it has proven a more challenging target for drug development. “Overall the prospects for a successful treatment in HFpEF patients do not look good as the pathophysiology of the disease is poorly understood. HFpEF is considered a heterogeneous disease prompted by a burden of comorbidities, genetic predisposition and lifestyle factors. This makes identifying a novel mode of action that is effective in a broad range of HFpEF patients increasingly difficult,” observed Cohen.
PARAGON-HF studied ambulatory patients with established HFpEF being treated for symptoms and comorbidities; around half had a history of heart failure hospitalizations.
Novartis continues to run two additional Phase III trials of Entresto in HFpEF. PARAGLIDE-HF is studying the drug compared with valsartan when initiated in hospitalized patients with acute decompensated heart failure who have been stabilized during hospitalization; endpoints are changes in NT-proBNP and safety and tolerability. PARALLAX is studying Entresto versus valsartan, or enalapril, or placebo; its endpoints are changes in NT-proBNP at week 12 and changes from baseline in 6-minute walk distance at week 24.
Entresto is an oral pill combining the angiotensin II receptor blocker (ARB) valsartan, marketed by Novartis as Diovan for heart failure in the US since 2002, and sacubitril, a prodrug that inhibits the enzyme neprilysin, which is responsible for the breakdown of several vasoactive peptides.
One positive to be drawn from the PARAGON-HF trial update was that no new safety or tolerability issues emerged, indicating that it will not have a negative impact on the product’s ongoing use in HFrEF.
Other Contenders: Lilly/Boehringer And AstraZeneca
Other companies running advanced trials in HFpEF include Boehringer Ingelheim GmbH and Eli Lilly & Co., which recently won fast track status for their SGLT2 inhibitor Jardiance (empagliflozin), and AstraZeneca PLC, with another SGLT2 inhibitor Farxiga (dapagliflozin). The Phase III EMPEROR-Preserved trial of Jardiance is expected to read out in 2020, while results from the DELIVER trial of Farxiga are expected in 2021. Jardiance is being studied for time to first event (cardiovascular death or hospitalization for heart failure) versus placebo, while Farxiga is being studied studied for its ability to reduce cardiovascular death or worsening heart failure compared with placebo.